OBJECTIVE:To examine in a major cohort of patients whether or not musculoskeletal adverse effects (MAEs), similar to those seen in intravenous bisphosphonates (BP), might occur also in high dosage oral treatment regimens with alendronate (ALN) and risedronate (RSN).PATIENTS AND METHODS:612 consecutive patients treated in the osteoporosis outpatient clinic at Charite, Campus Benjamin Franklin, between July 2002 and October 2003 with oral ALN or RSN (mean age 68.2+/-9.7 years; 527 females, 85 males), were examined and followed up for MAEs.RESULTS:The overall frequency of any severe MAEs in our patients was low (5.6%). All severe MAEs occurred in primarily once weekly treated patients: 27 in ALN 70 mg once weekly (27/134=20.1%) and 7 in RSN 35 mg once weekly (7/28=25.0%), with no significant difference between those groups. The most frequently reported MAE was acute arthralgia in 12.6%, followed by acute back pain in 9.1% of all primarily once weekly treated cases. None of the 302 patients initially treated with daily BP reported any MAEs when later switching to once weekly administration (218 patients to ALN 70 mg once weekly and 84 patients to RSN 35 mg once weekly). With reference to recently published data, the phenomenon is probably related to dose dependent gammadelta T cell activation by accumulation of isopentenyl pyrophosphate (IPP) due to inhibition of the mevalonate pathway by nitrogen containing bisphosphonates (nBP).CONCLUSIONS:MAEs in oral BP are, in general, less common and severe than in intravenous BP. They are observed exclusively in patients starting ALN or RSN treatment with once weekly dosage regimens. In order to avoid this phenomenon, it is suggested to start ALN or RSN treatment with the lower daily dosages of ALN 10 mg daily or RSN 5 mg daily for about two weeks before switching to the overall, more convenient, once weekly dose regimen.

It is a truism infrequently acknowledged that few things are more difficult than to predict a fracture event. Indeed, the greater the accuracy of prediction required, the greater the difficulty is. In considering the associations between various quantitative ultrasound (QUS) measurements and asymptomatic vertebral fracture reported by Glüer et al., we see no reason to challenge their carefully worded conclusion and judgment, but here we would like to put forward a few heuristic points that may yield some alternative and supplementary interpretations. First, in many clinical and epidemiologic settings, odds ratio (OR) can be used as an estimate of risk ratio (RR). If p1 is the prevalence of fracture exposed to a risk factor (i.e., low speed of sound [SOS]) and p0 is the prevalence of fracture unexposed to the risk factor, then RR p1/p0 and OR p1/(1 − p1)/p0/(1 − p0). Therefore, it is easier to understand the meaning of a RR than that of OR. For example, an RR of 1.7 readily informs us that the risk of fracture in the exposed group is 70% higher than the risk in the unexposed group. However, for an OR of 1.7, an equivalent interpretation of increased risk is not tractable, because the unit of interpretation is now odds, not probability (i.e., the odds of sustaining a fracture in the exposed group is 70% higher than the odds of sustaining a fracture in the unexposed group). Because of this awkward interpretation, some authors suggest that OR is meaningless, whereas others suggest that OR should not be used as a measure of strength of association. Second, OR usually overestimates RR. For events with low frequency in the population (e.g., hip fracture), where 1 − p1 and 1 − p0 are close to 1, OR is approximately equal to RR; however, when the prevalence of fracture is high, the OR actually overestimates the RR, and in practice, such an overestimate has generated misunderstanding about the magnitude of association in the scientific media as well as in the popular press. The study by Glüer et al. is a case in point; they report that the unadjusted OR for the association between Achilles + SOS and fracture was 1.7, but with the prevalence of fracture of 16%, the RR was actually around 1.5. Therefore, all of the ORs reported by Glüer et al. in their Table 2 actually overestimate the actual strength of association between QUS (and for that matter, DXA measurement of BMD) and fracture risk. Third, RR (or its estimate, OR) is primarily a measure of association of two variables, not a measure of discrimination of two events. Consequently, a risk factor with a high OR is not necessarily an accurate discriminator of fracture cases from nonfracture cases. In the following simulations, using the parameters similar to the study of Glüer et al., we show that, for an OR of 1.7, the proportion of SOS values in fracture and nonfracture cases overlapping is ∼80%. This overlapping proportion is, as expected, progressively decreased as the OR increases. However, even with an OR of 10, the overlapping proportion is still high (∼20%). To achieve a complete discrimination between fracture and nonfracture cases, an OR of 30 is required (Fig. 1). Therefore, it can be argued that none of the QUS or DXA BMD measurements was qualified as an accurate discriminator of fracture. Fourth, in addition to OR, Glüer et al. used the area under the receiver operating characteristic (ROC) curve to gauge the use of QUS in the identification of fracture. In this study, the area under the ROC curve, although in the modest range (between 0.6 and 0.7), was likely optimistic, because the regression-based discrimination rule was derived and applied to the same data set. The modus operandi of the logistic regression is that its parameters are estimated from observed data such that they maximize the likelihood of the observed data. Thus, when the logistic regression equation is used to generate a discrimination rule and if the rule is applied to the same data set (which is the case in the study of Glüer et al.), the discrimination rule would naturally yield the best concordance with the observed data. Therefore, the area under the ROC curve is only meaningful when the discrimination rule is applied to an independent sample. Moreover, the ROC curve is a trade-off between sensitivity and complement of specificity (i.e., false positive rate). Sensitivity is the proportion fracture cases who are identified as “high risk” by, in this case, the QUS measurement; specificity is the proportion of nonfracture individuals who are identified by the QUS as “low risk.” Both sensitivity and specificity do not answer the question of interest: given a group of individuals with “high risk” (or “low risk”) values of QUS, how many of them will sustain a fracture? To answer this question, we need to take into account the prevalence of fracture and estimate the positive predictive value (PPV), which can be shown as a function of fracture prevalence, OR, and sensitivity or specificity (Fig. 2). (A proof can be obtained by e-mailing the authors.) In the study of Glüer et al., all ORs were <2, and for a fracture prevalence of 16%, the PPV was likely <0.2, which is very low for identification of fracture cases. Even with the combination of QUS and BMD, the PPV is still <0.3, suggesting that such a combination does not provide an accurate discrimination. Finally, we would like to make a comment on the interpretation by Glüer et al. Based on the estimates of the logistic regression parameters, Glüer et al. state, as an example of interpretation, that “For example, two women JOURNAL OF BONE AND MINERAL RESEARCH Volume 20, Number 3, 2005 Published online on November 29, 2004; doi: 10.1359/JBMR.041130 © 2005 American Society for Bone and Mineral Research

UNLABELLED:We compared the performance of five QUS devices with DXA in a population-based sample of 2837 women. All QUS approaches discriminated women with and without osteoporotic vertebral fractures. QUS of the calcaneus performed as well as central DXA. INTRODUCTION:Quantitative ultrasound (QUS) methods have found widespread use for the assessment of bone status in osteoporosis, but their optimal use remains to be established. To determine QUS performance for current devices in direct comparison with central DXA, we initiated a large population-based investigation, the Osteoporosis and Ultrasound Study (OPUS). MATERIALS AND METHODS:A total of 463 women 20-39 years of age and 2374 women 55-79 years of age were measured on five different QUS devices along with DXA of the spine and the proximal femur. Their vertebral fracture status was evaluated radiographically. The association of QUS and DXA with vertebral fracture status was evaluated using logistic regression. RESULTS:All QUS approaches tested discriminated women with and without osteoporotic vertebral fractures (20% height reduction), with age-adjusted standardized odds ratios ranging 1.2-1.3 for amplitude-dependent speed of sound (AD-SOS) at the finger phalanges, 1.2-1.4 for broadband ultrasound attenuation (BUA) at the calcaneus, and 1.4-1.5 for speed of sound (SOS) at the calcaneus, 1.4-1.6 for DXA of the total femur, and 1.5-1.6 for DXA at the spine. For more severe fractures (40% height reduction), age-adjusted standardized odds ratios increased to up to 1.9 for DXA of the spine and 2.3 for SOS of the calcaneus. CONCLUSIONS:In conclusion, all five QUS devices tested showed significant age-adjusted differences between subjects with and without vertebral fracture. When selecting the strongest variable, QUS of the calcaneus worked as well as central DXA for identification of women at high risk for prevalent osteoporotic vertebral fractures. QUS-based case-finding strategies would allow halving the number of radiographs in high-risk populations, and this strategy works increasingly well for women with more severe vertebral fractures. It is likely that the good performance of QUS was in part achieved by rigorous quality assurance measures that should also be used in clinical practice.